Project Abstract Autism spectrum disorder (ASD) is a heterogeneous condition affecting approximately 1 in 59 children in the US. ASD is characterized by deficits in social interactions, repetitive behaviors and/or restricted interests, and is often associated with intellectual disability. Although ASD is clearly developmental, with diagnoses typically occurring by 2-3 years of age, most people do not outgrow the diagnosis and continue to suffer with dysfunction in adulthood. Adults with ASD experience greater unemployment and social isolation than their peers with other developmental disorders, strongly supporting the need for therapies targeted to adults. A few studies have reported improvements in symptoms of ASD patients with interventions in adulthood, raising the possibility that plastic processes in the adult ASD brain may be enhanced to optimize function. Many brain regions have been implicated in ASD but among them the hippocampus is notable in that it is involved in both social and cognitive behavior and displays ongoing plasticity throughout life. Perineuronal nets (PNNs) are extracellular matrix structures that dampen plasticity and have been linked to neuropsychiatric disease. Studies have found evidence for mutations in genes associated with the extracellular matrix in ASD but previous work has not investigated whether PNNs contribute to social and cognitive dysfunction. Research indicates that PNNs and orthodenticle homeobox 2 (OTX2), a transcription factor important for PNN maintenance, are excessive in ASD mice in the hippocampal CA2 and CA3 regions, areas important for social and contextual/spatial processing. No studies have investigated whether interventions that normalize PNNs and OTX2 in the hippocampus mitigate problematic behaviors associated with ASD. Previous work suggests that ASD mice have reduced postnatal neurogenesis in the hippocampus and since adult-generated neurons contribute to social behavior as well as learning and memory, diminished adult neurogenesis may exacerbate ASD symptoms. Many target sites of new neurons in the hippocampus are surrounded by PNNs and since PNNs are known to inhibit plasticity, their over production in ASD may prevent optimal connections from forming. This proposal will address gaps in our understanding about how aberrant PNNs and their connections with adult-generated neurons contribute to behavioral dysfunction in ASD mice. The experiments will use transgenic and inbred ASD mouse models, manipulations of PNNs and OTX2, retroviral labeling of new neurons, immunolabeling with confocal and electron microscopy, drug and experiential stimulation of neurogenesis and behavioral analyses to explore the efficacy of interventions to mitigate ASD symptoms by normalizing PNNs, reducing OTX2 and optimizing connections between new neurons and PNN+ targets. The proposed work will advance our understanding of how structural plasticity in the hippocampus may be enhanced in the service of improving social and cognitive dysfunction in adults with ASD.